Integrative characterization of microglial and astrocyte activation in autism

Multiple lines of evidence point to abnormal activation of astrocytes and microglia in individuals with autism spectrum disorders (ASDs). However, the functional significance of astrocyte and microglial activation in ASD, their role in disease pathogenesis, and their promise as targets for therapeutic intervention remain unknown. In this project, Michael Gandal plans to integrate basic and translational studies to characterize the fundamental properties of glial cell activation in ASD and to more fully understand their contribution to disease pathophysiology.

Gandal will perform genetic and transcriptomic profiling on a comprehensive collection of postmortem ASD brain tissue, comprising 11 cortical brain regions from 48 individuals with ASD and 49 matched controls, spanning ages 2 to 67 years. Analyses will characterize the spatial and temporal trajectory of microglial and astrocyte activation in ASD, to understand when and where such changes arise in the brain and how this relates to critical developmental periods. Results will be integrated with polygenic risk scores to assess whether glial cell changes are driven by underlying genetic risk factors for ASD.

Finally, to determine the clinical significance of glial cell changes, a proof-of-principle clinical study will be performed in parallel, comparing in vivo levels of microglial activation with cognitive and behavioral measures in a cohort of adult males with ASD and matched controls (n=15/group). Individuals will undergo positron emission tomography (PET) imaging using the radiotracer N-(2,5-dimethoxy-benzyl)-N-(5-fluoro-2-phenoxyphenyl)-acetamide, labeled with carbon-11 ([11C]-DAA1106), which binds to the mitochondrial translocator protein (TSPO) and is a known marker of activated microglia in vivo. Individuals will also undergo a comprehensive set of cognitive and behavioral assessments to determine whether microglial cell changes reflect core phenotypic features of ASD.

The results from this study will greatly expand our understanding of the neurobiological underpinnings of ASD and will directly interrogate astrocyte and microglial cell activation as potential biomarkers for targeted therapeutic intervention.